Ubiquitously expressed in different cells and tissues, microRNAs (miRNAs) have critical roles in various diseases; dysfunction of miRNAs has been linked to the onset and progression of human cancers, including lymphoma. In particular, miR-21 and miR-155 exhibit differential expression levels in cancers resulting in a demonstrated capability to affect cellular transformation and carcinogenesis by acting as miRNA oncogenes, or oncomiRs. In fact, cancers can become addicted to miR-21 and miR-155 such that oncogenesis is dependent on the overexpression of the oncomiR, and withdrawal of the oncomiR leads to cancer cell death or reversal of the malignant phenotype. Little is known about how they work to cause cancer and why tumors become addicted to them. This warrants further investigation to understand the relationships between miRNAs and cancer, but also to capitalize on fact that addictive oncomiRs may be potent therapeutic targets. There are two main goals of this proposal: (1) to elucidate the relationships between miR-21/155 and lymphoma, and (2) to develop a therapeutic technology to exploit the addiction of cancer to these oncomiRs. The specific aims of this project are (Aim 1) to test the hypothesis that elucidating miR-21 and miR-155 downstream targets and pathways will reveal the mechanisms involved in the onset and maintenance of lymphoma; and (Aim 2) to test the hypothesis that molecules targeting miR-21 or miR-155, which are delivered using nanoparticles, will have therapeutic effects in miR-addicted mouse models and in human lymphoma cell lines. To accomplish Aim 1, in vivo pathways impacted by miR-21 and 155 in lymphoma will be identified using unbiased screens in miR-addicted transgenic mouse models and human B cell lines. Using biochemical methods, miRNA targets will be identified by comparing the populations of cross-linked mRNA from B-cells over-expressing miR-21 or miR-155 to normal B-cells. The RNA sequences obtained will be examined for small indels and point mutations present in the tumors but not found in normal spleen or lymph tissue. Lastly, the information derived above will be cross-referenced with human lymphoma, by examining if the same downstream targets are also found altered in human pre-B-cell lymphoma cells. To accomplish Aim 2, a nanoparticle delivery system will be coated with novel molecules that improve tumor accumulation via low pH- induced targeting, and then loaded with anti-miRs against miR-21 and miR-155. The optimized nanoparticle formulations will be evaluated for tumor-targeted biodistribution and tumor regression in lymphoma mouse models. Lastly, the most efficacious formulations will be used to treat human lymphoma cell lines in vitro and in vivo in xenograft models. OncomiRs are powerful molecular tools that modulate a multitude of cancer- associated genes. Little is known about the underlying mechanisms of oncomiR addiction in cancers such as lymphoma. This proposal seeks to further dissect this phenomenon in order to provide insights into miRNA and cancer biology, as well as establish a new paradigm for miRNA-targeted cancer therapy.